Recently, injuries such as tendon or ligament ruptures in sports, traffic accidents, etc., are increasing. In regard to ligaments, since the anterior cruciate ligament (ACL) and the posterior cruciate ligament (PCL) are tissues that connect the femur to the tibia through a knee joint, when the ACL or PCL is ruptured, the stability of the knee joint cannot be maintained. Once ruptured, ligaments cannot be oversewn; therefore, in many cases, ligament reconstructive surgery is utilized to repair or replace injured ligaments.
For example, in ACL reconstructive surgery in which a damaged ACL is reconstructed by replacing it with a ligament graft, the patellar tendon with bone blocks is conventionally utilized as a graft. Such ACL reconstructive surgery allows rehabilitation to start early because the patellar tendon can function as a ligament when the bones attach to each other. However, the surgery also has disadvantages such as postoperative pain and muscle weakness.
In recent years, ACL reconstructive surgery that utilizes as a tendon graft, a hamstring tendon (knee flexor tendon, semitendinosus tendon, gracilis tendon), which is one of the muscle tendons used in bending the knees has been reported (for example, see Non Patent Literature 1). More specifically, the surgery includes the steps of forming a bone tunnel (hole) in the upper end of the tibia and the lower end of the femur, placing one end of the tendon graft in the femur side of the bone tunnel, and placing the other end of the tendon graft in the tibia side of the bone tunnel. Thus, the tendon graft runs between the femur and the tibia, and thereby functions. The tendon graft performs substantially the same function as the original ACL, thereby allowing the recovery of normal function in the knee joints. However, since the object of ACL reconstructive surgery is to reconstruct the normal ACL function and the kinematics of the knee joints, it is necessary to reconstruct the tendon-bone joint tissue in the part where the tendon graft comes in contact with the bone surface in the bone tunnel with enough strength.
For this reason, ACL reconstructive surgery has a disadvantage such that a long period of time is required before the tendon graft can function as a ligament.
As a drug for promoting the regeneration of tendon-bone junction tissue, BMP-2 (Bone Morphogenetic Protein-2: Non-Patent Literature 2), TGF-β1 (Transforming Growth Factor-β1: Non-Patent Literature 3), etc., are known; however, they have not yet been used in practice as a drug for promoting the regeneration of tendon-bone junction tissue.
HGF (Hepatocyte Growth Factor, hereinafter referred to as “HGF protein”) was first identified as a potent mitogen for mature hepatocytes, and was determined by DNA cloning in 1989 (Non-Patent Literatures 4 and 5). Thereafter, HGF has been reported as having various effects such as angiogenesis, cell differentiation, cell proliferation, anti-apoptosis, etc., in various tissues. As to its effect in tendon tissue, it is reported that when HGF gene plasmid DNA is introduced into a wound made in the center of rat patellar tendon, the orientation of the developing collagen fibers in the wound is improved (Non-Patent Literature 6). However, tendon-bone junction tissue has a structure different from the tendon itself, and is a complicated tissue to adhere (fixate or fuse) a bone and a tendon, which are completely different from each other histologically. Non-Patent Literature 6 does not disclose or suggest the regeneration of such complicated tendon-bone junction tissue. Further, HGF protein is reported to inhibit the expression of TGF-β1, which, as mentioned previously, is known as a drug that promotes the regeneration of tendon-bone junction tissue (Non Patent Literature 7).